Papers - Enoki, Yuki

CKD病態の骨格筋萎縮における尿毒素の関与とその分子機構

榎木 裕紀, 渡邊 博志, 荒毛 里歩, 杉本 龍星, 異島 優, 田中 元子, 松下 和孝, 深川 雅史, 小田切 優樹, 丸山 徹

日本腎臓学会誌 ((一社)日本腎臓学会)  57 ( 3 ) 540 - 540 2015.04

Accepted,  ISSN  0385-2385

p-Cresyl sulfate, a uremic toxin, causes vascular endothelial and smooth muscle cell damages by inducing oxidative stress

Watanabe, H., Miyamoto, Y., Enoki, Y., Ishima, Y., Kadowaki, D., Kotani, S., Nakajima, M., Tanaka, M., Matsushita, K., Mori, Y., Kakuta, T., Fukagawa, M., Otagiri, M. and Maruyama, T.

Pharmacol Res Perspect (Pharmacology Research and Perspectives)  3 ( 1 ) e00092 - 12 2015.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  2052-1707

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The major cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease. Here, p-Cresyl sulfate (PCS), a uremic toxin, is considered to be a risk factor for cardiovascular disease in CKD. However, our understanding of the vascular toxicity induced by PCS and its mechanism is incomplete. The purpose of this study was to determine whether PCS enhances the production of reactive oxygen species (ROS) in vascular endothelial and smooth muscle cells, resulting in cytotoxicity. PCS exhibited pro-oxidant properties in human umbilical vein endothelial cells (HUVEC) and aortic smooth muscle cells (HASMC) by enhancing NADPH oxidase expression. PCS also up-regulates the mRNA levels and the protein secretion of monocyte chemotactic protein-1 (MCP-1) in HUVEC. In HASMC, PCS increased the mRNA levels of alkaline phosphatase (ALP), osteopontin (OPN), core-binding factor alpha 1, and ALP activity. The knockdown of Nox4, a subunit of NADPH oxidase, suppressed the cell toxicity induced by PCS. The vascular damage induced by PCS was largely suppressed in the presence of probenecid, an inhibitor of organic anion transporters (OAT). In PCS-overloaded 5/6-nephrectomized rats, plasma MCP-1 levels, OPN expression, and ALP activity of the aortic arch were increased, accompanied by the induction of Nox4 expression. Collectively, the vascular toxicity of PCS can be attributed to its intracellular accumulation via OAT, which results in an enhanced NADPH oxidase expression and increased ROS production. In conclusion, we found for the first time that PCS could play an important role in the development of cardiovascular disease by inducing vascular toxicity in the CKD condition.

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Pleiotropic Effects of Levofloxacin, Fluoroquinolone Antibiotics, against Influenza Virus-Induced Lung Injury

Enoki, Y., Ishima, Y., Tanaka, R., Sato, K., Kimachi, K., Shirai, T., Watanabe, H., Chuang, V. T., Fujiwara, Y., Takeya, M., Otagiri, M. and Maruyama, T.

PLoS One (PUBLIC LIBRARY SCIENCE)  10 ( 6 ) e0130248 2015

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1932-6203

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Reactive oxygen species (ROS) and nitric oxide (NO) are major pathogenic molecules produced during viral lung infections, including influenza. While fluoroquinolones are widely used as antimicrobial agents for treating a variety of bacterial infections, including secondary infections associated with the influenza virus, it has been reported that they also function as anti-oxidants against ROS and as a NO regulator. Therefore, we hypothesized that levofloxacin (LVFX), one of the most frequently used fluoroquinolone derivatives, may attenuate pulmonary injuries associated with influenza virus infections by inhibiting the production of ROS species such as hydroxyl radicals and neutrophil-derived NO that is produced during an influenza viral infection. The therapeutic impact of LVFX was examined in a PR8 (H1N1) influenza virus-induced lung injury mouse model. ESR spin-trapping experiments indicated that LVFX showed scavenging activity against neutrophil-derived hydroxyl radicals. LVFX markedly improved the survival rate of mice that were infected with the influenza virus in a dose-dependent manner. In addition, the LVFX treatment resulted in a dose-dependent decrease in the level of 8-hydroxy-2'-deoxyguanosine (a marker of oxidative stress) and nitrotyrosine (a nitrative marker) in the lungs of virus-infected mice, and the nitrite/nitrate ratio (NO metabolites) and IFN-gamma in BALF. These results indicate that LVFX may be of substantial benefit in the treatment of various acute inflammatory disorders such as influenza virus-induced pneumonia, by inhibiting inflammatory cell responses and suppressing the overproduction of NO in the lungs.

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Possible false-negative results on therapeutic drug monitoring of phenytoin using a particle enhanced turbidimetric inhibition immunoassay in a patient with a high level of IgM

Hirata, K., Saruwatari, J., Enoki, Y., Iwata, K., Urata, Y., Aizawa, K., Ueda, K., Shirouzono, T., Imamura, M., Moriuchi, H., Ishima, Y., Kadowaki, D., Watanabe, H., Hirata, S., Maruyama, T. and Fukunaga, E.

Ther Drug Monit (Therapeutic Drug Monitoring)  36 ( 5 ) 553 - 5 2014.10

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0163-4356

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: In this report, the authors described the unusual case of a patient in whom the plasma phenytoin concentration was unexpectedly not detected on a particle-enhanced turbidimetric inhibition immunoassay (PETINIA) technique, a typical immunoassay for phenytoin. The plasma concentration was measured using PETINIA and high-performance liquid chromatography in a 69-year-old male patient treated with fosphenytoin intravenously at the standard dose for 7 days. Although the plasma concentration of phenytoin was below the limit of detection (<0.5 mcg/mL) on PETINIA after the administration of fosphenytoin, the trough plasma concentration was estimated to be between 5 and 10 mg/L on high-performance liquid chromatography. When the plasma concentrations of IgM and IgG were measured using an enzyme-linked immunosorbent assay, the plasma IgG level was within the reference range, whereas the plasma IgM level was 2-3 times higher than the upper limit of the reference range. We concluded that the PETINIA method yielded a possible false-negative result regarding the phenytoin level in this patient, perhaps because of some hindrance to the measurement process by IgM. This case suggests that false-negative results should be considered when therapeutic drug monitoring reveals abnormally low values using PETINIA and that it is necessary to evaluate the plasma IgM level.

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尿毒症物質p-クレジル硫酸の酸化ストレス誘導を介した血管障害作用

渡邊 博志, 宮本 洋平, 榎木 裕紀, 異島 優, 深川 雅史, 小田切 優樹, 丸山 徹

日本腎臓学会誌 ((一社)日本腎臓学会)  56 ( 3 ) 398 - 398 2014.05

Accepted,  ISSN  0385-2385

インフルエンザ肺炎に対するヒト血清アルブミン-チオレドキシン融合タンパク質の有効性評価

田中 遼大, 異島 優, 榎木 裕紀, 小田切 優樹, 渡邊 博志, 丸山 徹

日本薬剤学会年会講演要旨集 ((公社)日本薬剤学会)  29年会   163 - 163 2014.05

Accepted

インフルエンザ肺炎モデルマウスに対するヒト血清アルブミン-チオレドキシン融合タンパク質の有効性評価

異島 優, 田中 遼大, 榎木 裕紀, 小玉 あずさ, 来海 和彦, 渡邊 博志, 小田切 優樹, 丸山 徹

日本薬学会年会要旨集 ((公社)日本薬学会)  134年会 ( 4 ) 183 - 183 2014.03

Accepted,  ISSN  0918-9823

Therapeutic impact of human serum albumin-thioredoxin fusion protein on influenza virus-induced lung injury mice

Tanaka, R., Ishima, Y., Enoki, Y., Kimachi, K., Shirai, T., Watanabe, H., Chuang, V. T., Maruyama, T. and Otagiri, M.

Front Immunol (FRONTIERS RESEARCH FOUNDATION)  5 ( NOV ) 561 2014

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1664-3224

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Reactive oxygen species (ROS) are the primary pathogenic molecules produced in viral lung infections. We previously reported on the use of a recombinant human serum albumin (HSA)-thioredoxin 1 (Trx) fusion protein (HSA-Trx) for extending the half-life Trx, an endogenous protein with anti-oxidant properties. As a result, it was possible to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx. We hypothesized that HSA-Trx would attenuate the enhanced ROS production of species such as hydroxyl radicals by neutrophils during an influenza viral infection. The levels of 8-hydroxy-2'-deoxyguanosine and 3-nitrotyrosine were used as indices of the anti-oxidant activity of HSA-Trx. In addition, the cytoprotective effects of HSA-Trx were examined in PR8 (H1N1) influenza virus-induced lung injured mice. The findings show that HSA-Trx reduced the number of total cells, neutrophils, and total protein in BALF of influenza virus-induced lung injured mice. The HSA-Trx treatment significantly decreased the level of 8-hydroxy-2'-deoxyguanosine and 3-nitrotyrosine, but failed to inhibit inducible nitric oxide synthase expression, in the lungs of the virus-infected mice. On the other hand, Tamiflu((R)) treatment also significantly suppressed the production of inflammatory cells and neutrophil infiltration, as well as the protein level in BALF and lung histopathological alterations caused by the influenza virus. The suppressive effect of Tamiflu((R)) was slightly stronger than that of HSA-Trx. Interestingly, Tamiflu((R)) significantly decreased virus proliferation, while HSA-Trx had no effect. These results indicate that HSA-Trx may be of therapeutic value for the treatment of various acute inflammatory disorders such as influenza-virus-induced pneumonia, by inhibiting inflammatory-cell responses and suppressing the overproduction of NO in the lung.

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インフルエンザ肺障害に対するニューキノロン系抗菌薬の有効性評価

榎木 裕紀, 田中 遼大, 宮本 洋平, 異島 優, 渡邊 博志, 佐藤 圭創, 小田切 優樹, 丸山 徹

日本薬剤学会年会講演要旨集 ((公社)日本薬剤学会)  28年会   271 - 271 2013.04

Accepted